Chemogenetic control of gene expression and cell signaling with antiviral drugs

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Abstract

We describe the application of the NS3 cis -protease from hepatitis C virus (HCV) as a Ligand-Inducible Connection (LinC) that can be used to control the function and localization of engineered proteins in mammalian cells. The versatility of the approach is demonstrated in the design of drug-sensitive transcription factors (TFs) and transmembrane signaling proteins, the activities of which can be tightly and reversibly controlled using clinically-tested antiviral protease inhibitors.

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Most cited references 14

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Small Molecule-Triggered Cas9 Protein with Improved Genome-Editing Specificity

Kevin M Davis, Vikram Pattanayak, David Thompson … (2015)

Directly modulating the activity of genome-editing proteins has the potential to increase their specificity by reducing activity following target locus modification. We developed Cas9 nucleases that are activated by the presence of a cell-permeable small molecule by inserting an evolved 4-hydroxytamoxifen (4-HT)-responsive intein at specific positions in Cas9. In human cells, conditionally active Cas9s modify target genomic sites with up to 25-fold higher specificity than wild-type Cas9.

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Mechanical Allostery: Evidence for a Force Requirement in the Proteolytic Activation of Notch.

Wendy R Gordon, Brandon Zimmerman, Li-Li He … (2015)

Ligands stimulate Notch receptors by inducing regulated intramembrane proteolysis (RIP) to produce a transcriptional effector. Notch activation requires unmasking of a metalloprotease cleavage site remote from the site of ligand binding, raising the question of how proteolytic sensitivity is achieved. Here, we show that application of physiologically relevant forces to the Notch1 regulatory switch results in sensitivity to metalloprotease cleavage, and bound ligands induce Notch signal transduction in cells only in the presence of applied mechanical force. Synthetic receptor-ligand systems that remove the native ligand-receptor interaction also activate Notch by inducing proteolysis of the regulatory switch. Together, these studies show that mechanical force exerted by signal-sending cells is required for ligand-induced Notch activation and establish that force-induced proteolysis can act as a mechanism of cellular mechanotransduction.